1. Field of the Invention
This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
The following publications, patents and patent applications are cited in this publication as superscript numbers:
1 Hemler and Takada, European Patent Application Publication No. 330,506, published Aug. 30, 1989
2 Elices, et al., Cell, 60:577-584 (1990)
3 Springer, Nature, 346:425-434 (1990)
4 Osborn, Cell, 62:3-6 (1990)
5 Vedder, et al., Surgery, 106:509 (1989)
6 Pretolani, et al., J. Exp. Med., 180:795 (1994)
7 Abraham, et al., J. Clin. Invest., 93:776 (1994)
8 Mulligan, et al., J. Immunology, 150:2407 (1993)
9 Cybulsky, et al., Science, 25:788 (1991)
10 Li, et al., Arterioscler. Thromb., 13:197 (1993)
11 Sasseville, et al., Am. J. Path., 144:27 (1994)
12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)
13 Burkly, et al., Diabetes, 43:529 (1994)
14 Baron, et al., J. Clin. Invest., 93:1700 (1994)
15 Hamann, et al., J. Immunology, 152:3238 (1994)
16 Yednock, et al., Nature, 356:63 (1992)
17 Baron, et al., J. Exp. Med., 177:57 (1993)
18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)
19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993)
20 Elices, et al., J. Clin. Invest., 93:405 (1994)
21 Postigo, et al., J. Clin. Invest., 89:1445 (1991)
22 Paul, et al., Transpl. Proceed., 25:813 (1993)
23 Okarhara, et al., Can. Res., 54:3233 (1994)
24 Paavonen, et al., Int. J. Can., 58:298 (1994)
25 Schadendorf, et al., J. Path., 170:429 (1993)
26 Bao, et al., Diff., 52:239 (1993)
27 Lauri, et al., British J. Cancer, 68:862 (1993)
28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)
29 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
30 International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
2. State of the Art
VLA-4 (also referred to as xcex14xcex21 integrin and CD49d/CD29), first identified by Hemler and Takada1, is a member of the xcex21 integrin family of cell surface receptors, each of which comprises two subunits, an xcex1 chain and a xcex2 chain. VLA-4 contains an xcex14 chain and a xcex21 chain. There are at least nine xcex21 integrins, all sharing the same xcex21 chain and each having a distinct xcex1 chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 is unique among xcex21 integrins in that it also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA4 are responsible for the fibronectin and VCAM-1 binding activities, and each activity has been shown to be inhibited independently .2 
Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer3 and Osborn4.
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma6-8, Alzheimer""s disease, atherosclerosis9-10, AIDS dementia11, diabetes 12-14 (including acute juvenile onset diabetes), inflammatory bowel disease15 (including ulcerative colitis and Crohn""s disease), multiple sclerosis16-17, rheumatoid arthritis18-21, tissue transplantation22, tumor metastasis23-28, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
In view of the above, assays for determining the VLA-4 level in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions29,30. The present invention addresses these and other needs.
This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions, to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less (as measured by Example 95 below), which compounds are defined by formula I below: 
where
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R2 and R3 together with the nitrogen atom bound to R2 and the carbon atom bound to R3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl;
R5 is selected from the group consisting of xe2x80x94(CH2)n-aryl and xe2x80x94(CH2)n-heteroaryl, where n is an integer equal to 1 to 4;
Q is xe2x80x94C(X)NR7xe2x80x94 wherein R7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur;
and pharmaceutically acceptable salts thereof,
with the proviso that when R1 is 2,4,6-trimethylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring and Q is xe2x80x94C(O)NHxe2x80x94, then R5 is not benzyl; and
with the further proviso that when R1 is p-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring derived from D-proline and Q is xe2x80x94C(O)NHxe2x80x94, then R5 is not benzyl derived from D-phenylalanine.
In another embodiment, the compounds of this invention can also be provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of formula I is modified into a group which, in vivo, will convert to a carboxylic acid (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of formula IA: 
R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R2 and R3 together with the nitrogen atom bound to R2 and the carbon atom bound to R3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl;
R5 is selected from the group consisting of xe2x80x94(CH2)n-aryl and xe2x80x94(CH2)n-heteroaryl, where n is an integer equal to 1 to 4;
R6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, xe2x80x94O-(N-succinimidyl), xe2x80x94NH-adamantyl, xe2x80x94O-cholest-5-en-3-xcex2-yl, xe2x80x94NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, xe2x80x94NH(CH2)pCOOY where p is an integer of from 1 to 8 and Y is as defined above, xe2x80x94OCH2NR9R10 where R9 is selected from the group consisting of xe2x80x94C(O)-aryl and xe2x80x94C(O)-substituted aryl and R10 is selected from the group consisting of hydrogen and xe2x80x94CH2COOR11 where R11 is alkyl, and xe2x80x94NHSO2Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
Q is xe2x80x94C(X)NR7- wherein R7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur;
and pharmaceutically acceptable salts thereof,
with the following provisos:
A. when R1 is 4-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R5 is benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94NH(CH2)2CO2Et or -(1R,2S,5R)-(xe2x88x92)-menthyl ester;
B. when R1 is 4-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a 3-xcex2-phenyl-ring derived from D-proline, R5 is benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94OCH2CH3;
C. when R1 is 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R5 is benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94OCH3;
D. when R1 is 4-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R5 is D-benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94OCH2CH3;
E. when R1 is 4-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a 5,5-dimethyl-1,1-dioxo-thiaprolyl ring, R5 is benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94OC(CH3)3; and
F. when R1 is 4-methylphenyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring derived from D-proline, R5 is benzyl derived from D-phenylalanine and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94OCH3;
G. when R1 is n-butyl, R2 and R3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R5 is benzyl and Q is xe2x80x94C(O)NHxe2x80x94, then R6 is not xe2x80x94O-benzyl.
Preferably, in the compounds of formula I and IA above, R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. Even more preferably R1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH3C(O)NHxe2x80x94)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH3SC(xe2x95x90NH)]phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, and 4-(3xe2x80x2-dimethylamino-n-propoxy)-phenyl.
In one preferred embodiment, R2 and R3 together with the nitrogen atom bound to the R2 substituent and the carbon bound to the R3 substituent form a heterocyclic group or substituted heterocyclic group of 4 to 6 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur, which ring is optionally substituted with 1 to 2 substituents selected from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl and thiobenzyl, or can be fused to another saturated heterocyclic or cycloalkyl ring such as a cyclohexyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Such heterocyclic rings include thiazolidinyl (e.g., L-thiazolidin-4-yl), piperidinyl (e.g., L-piperidin-2-yl), piperizinyl (e.g., L-piperizin-2-yl), thiomorpholinyl (e.g., L-thiomorpholin-3-yl), pyrrolidinyl (e.g., L-pyrrolidin-2-yl), substituted pyrrolidinyl such as 4-hydroxypyrrolidinyl (e.g., 4-xcex1-(or xcex2-)hydroxy-L-pyrrolidin-2-yl), 4-fluoropyrrolidinyl (e.g., 4-xcex1-(or xcex2-)fluoro-L-pyrrolidin-2-yl), 3-phenylpyrrolidinyl (e.g., 3-xcex1-(or xcex2-)phenyl-L-pyrrolidin-2-yl), 3-thiophenylpyrrolidinyl (e.g., 3-xcex1-(or xcex2-)thiophenyl-L-pyrrolidin-2-yl), 4-aminopyrrolidinyl (e.g., 4-xcex1-(or xcex2-)amino-L-pyrrolidin-2-yl), 3-methoxypyrrolidinyl (e.g., 3-xcex1-(or xcex2-)methoxy-L-pyrrolidin-2-yl), 4,4-dimethylpyrrolidin-2-yl, substituted piperizinyl such as 4-N-Cbz-piperizin-2-yl, substituted thiazolidinyl such as 5,5-dimethylthiazolindin-4-yl, 1,1-dioxo-thiazolidinyl (e.g., L-1,1-dioxo-thiazolidin-4-yl), substituted 1,1-dioxo-thiazolidinyl such as L-1,1-dioxo-5,5-dimethylthiazolidin-4-yl, 1,1-dioxothiomorpholinyl (e.g., L-1,1-dioxo-thiomorpholin-3-yl) and the like. Preferably, such rings do not include those where R2 and R3 together with the nitrogen atom bound to R2 and the carbon atom bound to R3 form a azetidine ring.
Q is preferably xe2x80x94C(O)NHxe2x80x94 or xe2x80x94C(S)NHxe2x80x94.
R5 is preferably selected from all possible isomers arising by substitution of the following groups: benzyl, phenethyl, xe2x80x94CH2-(3-indolyl), xe2x80x94CH2-(1-naphthyl), xe2x80x94CH2-(2-naphthyl), xe2x80x94CH2-(2-thienyl), xe2x80x94CH2-(3-pyridyl), xe2x80x94CH2-(5-imidazolyl), xe2x80x94CH2-3-(1,2,4-triazolyl), xe2x80x94CH2-(2-thiazolyl) and the like.
In the compounds of formula IA, R6 is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-xcex1-iso-propyl-4-xcex2-methylcyclohexoxy, 2-xcex2-isopropyl-4-xcex2-methylcyclohexoxy, xe2x80x94NH2, benzyloxy, xe2x80x94NHCH2COOH, xe2x80x94NHCH2CH2COOH, xe2x80x94NH-adamantyl, xe2x80x94NHCH2CH2COOCH2CH3, xe2x80x94NHSO2-p-CH3-xcfx86, xe2x80x94NHOR8 where R8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), xe2x80x94O-cholest-5-en-3-xcex2-yl, xe2x80x94OCH2xe2x80x94OC(O)C(CH3)3, xe2x80x94O(CH2),NHC(O)W where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, and xe2x80x94NRxe2x80x3C(O)xe2x80x94Rxe2x80x2 where Rxe2x80x2 is aryl, heteroaryl or heterocyclic and Rxe2x80x3 is hydrogen or xe2x80x94CH2C(O)OCH2CH3.
Preferred compounds within the scope of formula I and IA above include by way of example:
N-(methanesulfonyl)-L-prolyl-L-phenylalanine
N-(xcex1-toluenesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-(N-methyl)phenylalanine
N-(toluene-4-sulfonyl)-L-pipecolinyl-L-phenylalanine
N-(toluene-4-sulfonyl)-D-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(4-hydroxy)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-D,L-homophenylalanine
N-(4-chlorobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(1-naphthalenesulfonyl)-L-prolyl-L-phenylalanine
N-(2-naphthalenelsulfonyl)-L-prolyl-L-phenylalanine
N-(4-methoxybenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-tert-butylbenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene4-sulfonyl)-L-(4-fluoro)prolyl-L-phenylalanine
N-(n-butanesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine
N-(2-methoxycarbonylbenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(2-carboxybenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-thiaprolyl-L-phenylalanine
N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-trifluoromethoxybenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(3,4-dichlorobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-D,L-(3-phenyl)prolyl-L-phenylalanine
N-(3,4-dimethoxybenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-nitrobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-acetamidobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-cyanobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-tryptophan
N-(toluene-4-sulfonyl)-L-prolyl-xcex2-(1-naphthyl)-L-alanine
N-(toluene-4-sulfonyl)-L-prolyl-xcex2-(2-naphthyl)-L-alanine
N-(toluene-4-sulfonyl)-L-prolyl-xcex2-(2-thienyl)-L-alanine
N-(isopropanesulfonyl)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-xcex2-(3-pyridyl)-L-alanine
N-(toluene-4-sulfonyl)-L-(4-phenylthio)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-(4-benzylthio)-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-histidine
N-(toluene-4-sulfonyl)-L-(4-amino)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninamide
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-methoxyamide
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-benzyloxyamide
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)amide
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninyl-xcex2-alanine
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-hydroxyaimide
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine isopropyl ester
N-(toluene-4-sulfonyl)-L-(4-hydroxy)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninyl-(N-benzoyl)glycine ethyl ester
N-(toluene-4-sulfonyl)-L-(4-fluoro)prolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-thiaprolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)tiaprolyl-L-phenylalanine ethyl ester
N-(2-methoxycarbonylbenzenesulfonyl)-L-prolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-(3-phenyl)prolyl-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(4-methoxy)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-prolyl-L- phenylalanine (1S,2R,5S)-(+)-menthyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-hydroxysuccinimide ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(nicotinamido)ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(1-methylpyridinium-3-amido)ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine cholesteryl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(1-methyl-1,4-dihydropyridinyl-3-amido)ethyl ester
N-(thiophene-2-sulfonyl)-L-prolyl-L-phenylalanine methyl ester
N-(thiophene-2-sulfonyl)-L-prolyl-L-phenylalanine
N-(5-chloro-1,3-dimethylpyrazole4-sulfonyl)-L-prolyl-L-phenylalanine
N-(2-phenylethanesulfonyl)-L-prolyl-L-phenylalanine
N-(1-methylimidazole-4-sulfonyl)-L-prolyl-L-phenylalanine methyl ester
N-(1-methylimidazole-4-sulfonyl)-L-prolyl-L-phenylalanine
N-(4-amidinobenzenesulfonyl)-L-prolyl-L-phenylalanine methyl ester
N-(4-amidinobenzenesulfonyl)-L-prolyl-L-phenylalanine
N-(4-thiomethoxyimidatylbenzene-4-sulfonyl)-L-prolyl-L-phenylalanine methyl ester
N-[4-(N-methylthioamido)benzenesulfonyl]-L-prolyl-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-prolyl-D,L-xcex2-(1,2,4-triazol-3-yl)alanine
N-(toluene-4-sulfonyl)-L-prolyl-D,L-xcex2-(thiazol-2-yl)alanine
N-[4-(3-dimethylaminopropyloxy)benzenesulfonyl]-L-prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-pyrrolidin-2-yl-thiocarbonyl-L-phenylalanine
N-(4-thiocarbamoylbenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine benzyl ester
N-(4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine benzyl ester
N-(toluene-4-sulfonyl)-L-prolyl-D-phenylalanine
N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-L-phenylalanine
N-(toluene-4-sulfonyl)-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-L-phenylalanine
N-(toluene-4-sulfonyl)-L-(5,5-dimethyl-1,1-dioxo)thiaprolyl-L-phenylalanine
N-(toluene4-sulfonyl)-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine tert-butyl ester
N-(toluene-4-sulfonyl)-L-pyrrolidin-2-yl-thiocarbonyl-L-phenylalanine methyl ester
N-(benzenesulfonyl)-L-prolyl-L-phenylalanine methyl ester
N-(toluene-4-sulfonyl)-L-(5-oxo)prolyl-L-phenylalanine ethyl ester
N-(toluene-4-sulfonyl)-L-(5-oxo)prolyl-L-phenylalanine
and pharmaceutically acceptable salts thereof, as well as any of the ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester.
This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or IA above under conditions wherein said compound binds to VLA4.
Certain of the compounds of formula I and IA above are also useful in reducing VLA-4 mediated inflammation in vivo.
This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or IA above, with the exception that R3 and R5 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used.
The pharmaceutical compositions may be used to treat VLA4 mediated disease conditions. Such disease conditions include, by way of example, asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above.
Preferred compounds of formula I and IA above include those set forth in Table I below:
As above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. However, prior to describing this invention in further detail, tile following terms will first be defined.
Definitions
As used herein, xe2x80x9calkylxe2x80x9d refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2-NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and allyl/substituted alkyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-Oxe2x80x94xe2x80x9d which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-Oxe2x80x94xe2x80x9d.
xe2x80x9cAcylxe2x80x9d refers to the groups Hxe2x80x94C(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, alkynyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94 cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, substituted aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, substituted heteroaryl-C(O), heterocyclic-C(O)xe2x80x94, and substituted heterocyclic-C(O)xe2x80x94, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cThiocarbonylaminoxe2x80x9d refers to the group xe2x80x94C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, alkenyl-C(O)Oxe2x80x94, substituted alkenyl-C(O)Oxe2x80x94, alkynyl-C(O)Oxe2x80x94, substituted alkynyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, substituted aryl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, substituted heteroaryl-C(O)Oxe2x80x94, heterocyclic-C(O)Oxe2x80x94, and substituted heterocyclic-C(O)Oxe2x80x94, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAlkenylxe2x80x9d refers to an alkenyl group preferably having from 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and having at least 1, and preferably from 1-2, sites of alkenyl unsaturation.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2-N-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and alkenyl/substituted alkenyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAlkynylxe2x80x9d refers to an alkynyl group preferably having from 2 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms, and having at least 1, and preferably from 1-2, sites of alkynyl unsaturation.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAmidinoxe2x80x9d refers to the group 
and the term xe2x80x9calkylamidinoxe2x80x9d refers to compounds having 1 to 3 alkyl groups (e.g., 
xe2x80x9cThioamidinoxe2x80x9d refers to the group 
where R is hydrogen or alkyl.
xe2x80x9cAminoacylxe2x80x9d refers to the groups xe2x80x94NRC(O)alkyl, xe2x80x94NRC(O)substituted alkyl, xe2x80x94NRC(O)cycloalkyl, xe2x80x94NRC(O)substituted cycloalkyl, xe2x80x94NRC(O)alkenyl, xe2x80x94NRC(O)substituted alkenyl, xe2x80x94NRC(O)alkynyl, xe2x80x94NRC(O)substituted alkynyl, xe2x80x94NRC(O)aryl, xe2x80x94NRC(O)substituted aryl, xe2x80x94NRC(O)heteroaryl, xe2x80x94NRC(O)substituted heteroaryl, xe2x80x94NRC(O)heterocyclic, and xe2x80x94NRC(O)substituted heterocyclic where R is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonyloxyxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-alkenyl, xe2x80x94NRC(O)O-substituted alkenyl, xe2x80x94NRC(O)O-alkynyl, xe2x80x94NRC(O)O-substituted alkynyl, xe2x80x94NRC(O)O-cycloalkyl, xe2x80x94NRC(O)O-substituted cycloalkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-substituted aryl, xe2x80x94NRC(O)O-heteroaryl, xe2x80x94NRC(O)O-substituted heteroaryl, xe2x80x94NRC(O)O-heterocyclic, and xe2x80x94NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxycarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH2, xe2x80x94OC(O)NRR, xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NR-substituted alkyl, xe2x80x94OC(O)NR-alkenyl, xe2x80x94OC(O)NR-substituted alkenyl, xe2x80x94OC(O)NR-alkynyl, xe2x80x94OC(O)NR-substituted alkynyl, xe2x80x94OC(O)NR-cycloalkyl, xe2x80x94OC(O)NR-substituted cycloalkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-substituted aryl, xe2x80x94OC(O)NR-heteroaryl, xe2x80x94OC(O)NR-substituted heteroaryl, xe2x80x94OC(O)NR-heterocyclic, and xe2x80x94C(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cOxythiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94OC(S)NH2, xe2x80x94OC(S)NRR, xe2x80x94OC(S)NR-alkyl, xe2x80x94OC(S)NR-substituted alkyl, xe2x80x94OC(S)NR-alkenyl, xe2x80x94OC(S)NR-substituted alkenyl, xe2x80x94OC(S)NR-alkynyl, xe2x80x94OC(S)NR-substituted alkynyl, xe2x80x94OC(S)NR-cycloalkyl, xe2x80x94OC(S)NR-substituted cycloalkyl, xe2x80x94OC(S)NR-aryl, xe2x80x94OC(S)NR-substituted aryl, xe2x80x94OC(S)NR-heteroaryl, xe2x80x94OC(S)NR-substituted heteroaryl, xe2x80x94OC(S)NR-heterocyclic, and xe2x80x94OC(S)NR-substituted heterocyclic where R is hydrogen or allyl, or where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitute-d alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(O)NRR, xe2x80x94NRC(O)NR-alkyl, xe2x80x94NRC(O)NR-substituted alkyl, xe2x80x94NRC(O)NR-alkenyl, xe2x80x94NRC(O)NR-substituted alkenyl, xe2x80x94NRC(O)NR-alkynyl, xe2x80x94NRC(O)NR-substituted alkynyl, xe2x80x94NRC(O)NR-aryl, xe2x80x94NRC(O)NR-substituted aryl, xe2x80x94NRC(O)NR-cycloalkyl, xe2x80x94NRC(O)NR-substituted cycloalkyl, xe2x80x94NRC(O)NR-heteroaryl, xe2x80x94NRC(O)NR-substituted heteroaryl, xe2x80x94NRC(O)NR-heterocyclic, and xe2x80x94NRC(O)NR-substituted heterocyclic where each R is independently hydrogen or alkyl, or where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cAminothiocarbonylaminoxe2x80x9d refers to the groups xe2x80x94NRC(S)NRR, xe2x80x94NRC(S)NR-alkyl, xe2x80x94NRC(S)NR-substituted alkyl, xe2x80x94NRC(S)NR-alkenyl, xe2x80x94NRC(S)NR-substituted alkenyl, xe2x80x94NRC(S)NR-alkynyl, xe2x80x94NRC(S)NR-substituted alkynyl, xe2x80x94NRC(S)NR-aryl, xe2x80x94NRC(S)NR-substituted aryl, xe2x80x94NRC(S)NR-cycloalkyl, xe2x80x94NRC(S)NR-substituted cycloalkyl, xe2x80x94NRC(S)NR-heteroaryl, xe2x80x94NRC(S)NR-substituted heteroaryl, xe2x80x94NRC(S)NR-heterocyclic, and xe2x80x94NRC(S)NR-substituted heterocyclic where each R is independently hydrogen or alkyl, or where each R is joined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d or xe2x80x9cArxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls include phenyl and naphthyl.
xe2x80x9cSubstituted arylxe2x80x9d refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 which includes, by way of example, phenoxy, naphthoxy, and the like.
xe2x80x9cSubstituted aryloxyxe2x80x9d refers to substituted aryl-Oxe2x80x94 groups.
xe2x80x9cAryloxyarylxe2x80x9d refers to the group -aryl-O-aryl
xe2x80x9cSubstituted aryloxyarylxe2x80x9d refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or allyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
xe2x80x9cSubstituted cycloalkylxe2x80x9d and xe2x80x9csubstituted cycloalkenylxe2x80x9d refer to cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cCycloalkoxyxe2x80x9d refers to xe2x80x94O-cycloalkyl groups.
xe2x80x9cSubstituted cycloalkoxyxe2x80x9d refers to xe2x80x94O-substituted cycloalkyl groups.
xe2x80x9cGuanidinoxe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRR, xe2x80x94NRC(xe2x95x90NR)NR-alkyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NR-alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NR-alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NR-aryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NR-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NR-substituted cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NR-heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NR-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cGuanidinosulfonexe2x80x9d refers to the groups xe2x80x94NRC(xe2x95x90NR)NRSO2-alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkenyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted alkynyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted aryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted cycloalkyl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heteroaryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heteroaryl, xe2x80x94NRC(xe2x95x90NR)NRSO2-heterocyclic, and xe2x80x94NRC(xe2x95x90NR)NRSO2-substituted heterocyclic where each R is independently hydrogen and alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl.
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94S(O)2-alkyl, xe2x80x94S(O)2-substituted alkyl, xe2x80x94S(O)2-cycloalkyl, xe2x80x94S(O)2-substituted cycloalkyl, xe2x80x94S(O)2-alkenyl, xe2x80x94S(O)2-substituted alkenyl, xe2x80x94S(O)2-aryl, xe2x80x94S(O)2-substituted aryl, xe2x80x94S(O)2-heteroaryl, xe2x80x94S(O)2-substituted heteroaryl, xe2x80x94S(O)2-heterocyclic, xe2x80x94S(O)2-substituted heterocyclic, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted allyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, or substituted with xe2x80x94SO2NRR where R is hydrogen or alkyl.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to the group xe2x80x94O-heteroaryl and xe2x80x9csubstituted heteroaryloxyxe2x80x9d refers to the group xe2x80x94O-substituted heteroaryl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a saturated or unsaturated group having a single ring or multiple condensed rings having from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl.
xe2x80x9cSaturated heterocyclicxe2x80x9d refers to heterocycles of single or multiple condensed rings lacking unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
xe2x80x9cUnsaturated heterocyclicxe2x80x9d refers to non-aromatic heterocycles of single or multiple condensed rings having unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
xe2x80x9cSubstituted heterocyclicxe2x80x9d refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (xe2x95x90O), thioxo (xe2x95x90S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where R is hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR-heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic and xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and alkynyl/substituted alkynyl groups substituted with xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-alkenyl, xe2x80x94SO2-substituted alkenyl, xe2x80x94SO2-cycloalkyl, xe2x80x94SO2-substituted cycloalkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-substituted aryl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-substituted heteroaryl, xe2x80x94SO2-heterocyclic, xe2x80x94SO2-substituted heterocyclic and xe2x80x94SO2NRR where R is hydrogen or alkyl.
Examples of heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cSaturated substituted heterocyclicxe2x80x9d refers to substituted heterocycles of single or multiple condensed rings lacking unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
xe2x80x9cUnsaturated substituted heterocyclicxe2x80x9d refers to non-aromatic substituted heterocycles of single or multiple condensed rings having unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
xe2x80x9cHeterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-heterocyclic and xe2x80x9csubstituted heterocyclyloxyxe2x80x9d refers to the group xe2x80x94O-substituted heterocyclic.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH,
xe2x80x9cThioalkylxe2x80x9d refers to the groups xe2x80x94S-alkyl
xe2x80x9cSubstituted thioalkylxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThocycloalkylxe2x80x9d refers to the groups xe2x80x94S-cycloalkyl.
xe2x80x9cSubstituted thiocycloalkylxe2x80x9d refers to the group xe2x80x94S-substituted cycloalkyl.
xe2x80x9cThioarylxe2x80x9d refers to the group xe2x80x94S-aryl and xe2x80x9csubstituted thioarylxe2x80x9d refers to the group xe2x80x94S-substituted aryl.
xe2x80x9cThioheteroarylxe2x80x9d refers to the group xe2x80x94S-heteroaryl and xe2x80x9csubstituted thioheteroarylxe2x80x9d refers to the group xe2x80x94S-substituted heteroaryl.
xe2x80x9cThioheterocyclicxe2x80x9d refers to the group xe2x80x94S-heterocyclic and xe2x80x9csubstituted thioheterocyclicxe2x80x9d refers to the group xe2x80x94S-substituted heterocyclic.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of formula I or IA, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound of formula I or IA contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
Compound Preparation
The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where topical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of His invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
In a preferred method of synthesis, the compounds of formulas I and IA, wherein Q is xe2x80x94C(O)NR7xe2x80x94, are prepared by first coupling an amino acid of formula II: 
wherein R2 and R3 are as defined in formulas I and IA, and R4 is hydrogen, with a sulfonyl chloride of formula III:
R1xe2x80x94SO2xe2x80x94Clxe2x80x83xe2x80x83III
wherein R1 is as defined in formulas I and IA, to provide an N-sulfonyl amino acid of formula IV: 
wherein R1-R4 are as defined above.
This reaction is typically conducted by reacting the amino acid of formula II with at least one equivalent, preferably about 1.1 to about 2 equivalents, of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Daumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. Upon completion of the reaction, the resulting N-sulfonyl amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like.
The amino acids of formula II employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Examples of suitable amino acids for use in this reaction include, but are not limited to, L-proline, trans4-hydroxyl-L-proline, cis-4-hydroxyl-L-proline, trans-3-phenyl-L-proline, cis-3-phenyl-L-proline, L-(2-methyl)proline, L-pipecolinic acid, L-indoline-2-carboxylic acid, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-(5,5-dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid, glycine, 2-tert-butylglycine, D,L-phenylglycine, L-alanine, xcex1-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D,L-phenylsarcosine, L-aspartic acid xcex2-tert-butyl ester, L-glutamic acid xcex3-tert-butyl ester, L-(O-benzyl)serine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid (cycloleucine) 1-aminocyclohexanecarboxylic acid, L-serine and the like. If desired, the corresponding carboxylic acid esters of the amino acids of formula II, such as the methyl esters, ethyl esters and the like, can be employed in the above reaction with the sulfonyl chloride III. Subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, i.e., treatment with an alkali metal hydroxide in an inert diluent such as methanol/water, then provides the N-sulfonyl amino acid IV.
Similarly, the sulfonyl chlorides of formula HI employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from compounds of the formula R1xe2x80x94SO3H where R1 is as defined above, using phosphorous trichloride and phosphorous pentachloride. This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 Be molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at a temperature in the range of about 0xc2x0 C. to about 80xc2x0 C. for about 1 to about 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chlorides of formula III can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R1xe2x80x94SH where R1 is as defined above, by treating the thiol with chlorine (Cl2) and water under conventional reaction conditions.
Examples of sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, xcex1-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl-4-tiiazolesulfonyl chloride, 1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the N-sulfonyl amino acids of formula IV.
The compounds of formula I are then prepared by coupling the intermediate N-sulfonyl amino acid of formula IV with an amino acid derivative of formula VI: 
wherein R5-R7 are as in formulas I and IA. This coupling reaction is typically conducted using well-known coupling reagents such as carbodiimides, BOP reagent (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like. Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and the like. If desired, polymer supported forms of carbodiimide coupling reagents may also be used including, for example, those described in Tetrahedron Letters, 34(48), 7685 (1993). Additionally, well-known coupling promoters, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, may be used to facilitate the coupling reaction.
This coupling reaction is typically conducted by contacting the N-sulfonylamino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably about 1 to about 1.2 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like. Generally, this reaction is conducted at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours. Upon completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
Alternatively, the N-sulfonyl amino acid IV can be converted into an acid halide and the acid halide coupled with amino acid derivative VI to provide compounds of formula I. The acid halide of VI can be prepared by contacting VI with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or, preferably, with oxalyl chloride under conventional conditions. Generally, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at temperature in the range of about 0xc2x0 C. to about 80xc2x0 C. for about 1 to about 48 hours. A catalyst, such as N,N-dimethylformamide, may also be used in this reaction.
The acid halide of N-sulfonyl amino acid IV is then contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like. Upon completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
Alternatively, the compounds of formula I can be prepared by first forming a diamino acid derivative of formula VII: 
wherein R2-R7 are as defined above. The diamino acid derivatives of formula VII can be readily prepared by coupling an amino acid of formula II with an amino acid derivative of formula VI using conventional amino acid coupling techniques and reagents, such as carbodiimides, BOP reagent and the like, as described above. Diamino acid VII can then be sulfonated using a sulfonyl chloride of formula III and using the synthetic procedures described above to provide a compound of formula I.
The amino acid derivatives of formula VI employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives of formula VI can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wis., USA) with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenylalanine isopropyl ester, L-phenylalanine benzyl ester, L-phenylalaninamide, N-methyl-L-phenylalanine benzyl ester, D,L-homophenylalanine methyl ester, xcex2-(1-naphthyl)-L-alanine methyl ester, xcex2-(2-naphthyl)-L-alanine methyl ester, xcex2-(2-thienyl)-L-alanine methyl ester, xcex2-(2-pyridyl)-L-alanine methyl ester, xcex2-(3-pyridyl)-L-alanine methyl ester, xcex2-(4-pyridyl)-L-alanine methyl ester, xcex2-(2-thiazolyl)-D,L-alanine methyl ester, xcex2-(1,2,4-triazol-3-yl)-D,L-alanine methyl ester, and the like. If desired, of course, other esters or amides of the above-described compounds may also be employed.
For ease of synthesis, the compounds of formula I are typically prepared as an ester, i.e., where R6 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature ranging from about 0xc2x0 C. to about 24xc2x0 C. for about 1 to about 12 hours. Alternatively, benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon. The resulting carboxylic acids may be coupled, if desired, to amines such as xcex2-alanine ethyl ester, hydroxyamines such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine, and the like, using conventional coupling reagents and conditions as described above.
As will be apparent to those skilled in the art, other functional groups present on any of the substituents of the compounds of formula I can be readily modified or derivatized either before or after the above-described coupling reactions using well-known synthetic procedures. For example, a nitro group present on a substituent of a compound of formula I or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. This reaction is typically conducted at a temperature of from about 20xc2x0 C. to about 50xc2x0 C. for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group on the R5 substituent can be prepared, for example, by using a 4-nitrophenylalanine derivative and the like in the above-described coupling reactions.
Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20xc2x0 C. to about 50xc2x0 C. for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid. Compounds having a pyridyl group can be readily prepared by using, for example, xcex2-(2-pyridyl)-, xcex2-(3-pyridyl)- or xcex2-(4-pyridyl)-L-alanine derivatives in the above-described coupling reactions.
By way of illustration, a compound of formula I, or an intermediate thereof, having a substituent containing a primary or secondary amino group, such as where R1 is a 4-aminophenyl group, can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, is used to facilitate the acylation reaction. Examples of carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonylnipecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-sulfonyl)-L-proline and the like.
Alternatively, a compound of formula I or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9270xc2x0 C. to about 40xc2x0 C. for about 1 to about 24 hours. If desired, an acylation catalyst such as 4-(N,N-dimethylamino)pyridine may be used to promote the acylation reaction. The acylation reaction is preferably conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
Examples of acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoromethylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride and the like. Carbamyl chlorides, such as N,N-dimethylcarbamyl chloride, N,N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates, such as di-tert-butyl dicarbonate, may be employed to provide carbamates.
In a similar manner, a compound of formula I or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g.,  greater than Nxe2x80x94SO2xe2x80x94N less than ).
Additionally, a primary and secondary amino group present on a substituent of a compound of formula I, or an intermediate thereof, can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I), and the like.
Furthermore, when a compound of formula I or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0xc2x0 C. to about 50xc2x0 C. for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like.
In a similar manner, when a compound of formula I, or an intermediate thereof, has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like.
By way of example, a compound of formula I or an intermediate thereof having a substituent containing a hydroxyl group, such as where RI is a 4-hydroxyphenyl group, can be readily O-alkylated to form ethers. This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group. This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether. Generally, this reaction is conducted at a temperature ranging from about 60xc2x0 C. to about 150xc2x0 C. for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction.
Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl xcex1-bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N-ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N-dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N-benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)morpholine, 2-(hexamethyleneimino)ethyl chloride, 3-(N-methylpiperazine)propyl chloride, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine, 2-(4-hydroxy-4-phenylpiperidine)ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinemethyl tosylate and the like.
Alternatively, a hydroxyl group present on a substituent of a compound of formula I, or an intermediate thereof, can be O-alkylated using the Mitsunobu reaction. In this reaction, ail alcohol, such as 3-(N,N-dimethylamino)-1-propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about xe2x88x9210xc2x0 C. to about 5xc2x0 C. for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound, such as N-tert-butyltyrosine methyl ester, is then added and the reaction mixture is stirred at a temperature of about 0xc2x0 C. to about 30xc2x0 C. for about 2 to about 48 hours to provide the O-alkylated product.
In a similar manner, a compound of formula I, or an intermediate thereof, containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent, such as xylenes, at a temperature of about xe2x88x9225xc2x0 C. to about 10xc2x0 C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature ranging from about 10xc2x0 C. to about 30xc2x0 C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to a temperature from about 70xc2x0 C. to about 150xc2x0 C. for about 2 to about 24 hours to provide the diaryl ether.
Additionally, a hydroxy-containing compound can also be readily derivatized to form a carbamate. In one method for preparing such carbamates, a hydroxy compound of formula I, or an intermediate thereof, is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9225xc2x0 C. to about 0xc2x0 C. for about 0.5 to about 2.0 hours. Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine, provides the carbamate. Examples of amines suitable for using in this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.
Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperature ranging from about 25xc2x0 C. to about 70xc2x0 C. for about 2 to about 72 hours. Typically, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4-N,N-dimethylamino)pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.
Likewise, when a compound of formula I, or an intermediate thereof, contains a primary or secondary hydroxyl group, such hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides. For example, derivatives of 4-hydroxy-L-proline can be converted into the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives via nucleophilic displacement of the derivatized hydroxyl group. Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.
These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature of from about 0xc2x0 C. to about 70xc2x0 C. for about 1 to about 48 hours. The resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N,N-dimethylformamide and water, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (xe2x80x94NH2) compound.
Similarly, a tosylate group can be readily displaced by a thiol to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperature of from about 0xc2x0 C. to about 37xc2x0 C. for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinosulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0xc2x0 C. to about 37xc2x0 C. for about 12 to about 24 hours affords the corresponding fluoro compound.
Furthermore, a compound of formula I, or an intermediate thereof, having a substituent containing an iodoaryl group, for example, when R1 is a 4-iodophenyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24xc2x0 C. to about 30xc2x0 C. until the reaction is complete. This reaction is further described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445.
In some cases, the compounds of formula I, or intermediates thereof, may contain substituents having one or more sulfur atoms. Such sulfur atoms will be present, for example, when the amino acid of formula II employed in the above reactions is derived from L-thiazolidine-4-carboxylic acid, L-(5,5-dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid and the like. When present, such sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about xe2x88x9250xc2x0 C. to about 75xc2x0 C. for about 1 to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are described further in March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th Ed., pp. 1201-1202, Wiley Publisher (1992).
Lastly, the compounds of formula I, where Q is xe2x80x94C(S)NR7xe2x80x94, can be prepared by using an amino thionoacid derivative in place of amino acid II in the above described synthetic procedures. Such amino thionoacid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Chem., 61:9045-9048 (1996) and Brain, et al., J. Org. Chem., 62:3808-3809 (1997) and references cited therein.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds of formula I and IA are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I or IA above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored with syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following formulation examples illustrate the pharmaceutical compositions of the present invention.